So, this is a case of a 73-year-old, otherwise pretty healthy lady, who has a history of mild diabetes and diet control. She came with hematuria, fatigue, some weight lossnot very noticeable, but, upon questioning, she reported some weight loss. After a workup was finished, a CT scan of the abdomen showed a left kidney mass, approximately 5 cm in size. She had a left-sided radical nephrectomy, and it basically revealed a clear-cell type renal cell carcinoma, 5 cm in size, but it was invading the left renal vein. So, the patient was staged to have a T3N0M0 disease. There was no evidence of metastasis on CT scans or anywhere else, and she recovered pretty well from the surgery. And then she was seen again 3 months after. All the scans were negative, and she continued her follow-up for the next 9 months when she was found to have, on a routine surveillance scan, multiple new liver metastases. Her laboratory data were important for high calcium and anemia, and also because she had lost approximately 4 or 5 pounds of body weight.

So, looking at this patient who has now developed metastatic disease, if you look at the risk factors, she belongs to the intermediate- or the poor-risk category. She has a time of onset of metastasiswhich is less than a year&mdash;she has high calcium, and she has anemia, so she belongs to the poor-risk category&mdash;although you can argue that if it was really a poor risk or if it was intermediate risk, but technically speaking following the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) criteria, she belongs to the intermediate-risk category. Now she needs to start treatment because she has metastatic disease.

So, laboratory data revealed she had high calcium, but otherwise, they were pretty unremarkable. The patient was diagnosed to have intermediate-risk category disease because the time of onset of metastasis was within 1 year of original diagnosis and nephrectomy, and she had high calcium.

The laboratory data revealed she had high calcium, but other labs were pretty unremarkable. Given that she had an interval of less than 1 year between the original diagnosis of kidney cancer and nephrectomy, and also the metastatic disease and hypercalcemia, she belongs to or belonged to the intermediate-risk category, having had 2 of the IMDC risk factors. Now she needs to start treatment. She also had PD-L1expression testing done on the tumor, and the tumor was PD-L1&ndash;negativeso the tumor did not express PD-L.

So, she also had PD-L1 testing done on the tumor, and she was not found to have a PD-L1expressing tumor. The treatment that was chosen for her was cabozantinib at 60 mg daily. After 4 weeks of being on cabozantinib, she developed grade 2 diarrhea, and the cabozantinib doses were decreased to 40 mg per day.

Case of Rapidly Progressing mRCC

So, what factors did I keep in mind when I was making a treatment decision for this patient? I think the first one was the IMDC risk factorhow many risk factors she had. She had 2 risk factors: presence of onset of metastatic disease within 1 year of surgery&mdash;within 1 year of diagnosis of localized kidney cancer&mdash;and high calcium. However, I also looked at her performance status. She was doing really well. She did not have really a lot of symptoms. She wanted to have an independent lifestyle. She did not want to visit me in the hospital multiple times. And, very importantly for me, the tumor did not express PD-L. So, upon PD-L1 testing, the tumor expression of PD-L1 was less than 1%, so those were the factors that I kept in mind while making a clinical decision for cabozantinib in this case.

For this patient with a newly diagnosed metastatic renal cell carcinoma, how do I pick which 1 to choose from? I have sunitinib, pazopanib, and cabozantinib. And very soon, nivolumab with ipilimumab will be approved.

Choosing Therapy for mRCC

What is the rationale for choosing cabozantinib over the ipilimumab/nivolumab combination in this patient? So, first of all, the ipilimumab/nivolumab combination is not available. It&rsquo;s not FDA approved. Moving forward 2 months or 3 months, assuming this combination is approved, I still think cabozantinib would be a better choice in this given patient because the PD-L expression of the tumor was less than 1%. And if we look at the CheckMate-214 trial data, the progression-free survival was not experienced by those patients whose tumor did not express PD-L1. So, in my view, for this given patient, cabozantinib would be a better choice.

So, regarding safety and toxicity of cabozantinib versus the ipilimumab/nivolumab combination, I think these drugs are very different with their own safety and toxicity profile. Cabozantinib is a very traditional VEGF TKI, which also targets AXL and MET. And accordingly, we see toxicities more in line with VEGF TKIs, such as hand-foot syndrome, hypertension, fatigue, diarrhea, and so on. On the other hand, the ipilimumab/nivolumab combination is a very novel combination. It is an already established combination in metastatic melanoma, but for GU oncologists, it&rsquo;s a very novel combination with its own novel set of side effects and safety profile. Safety toxicity profile of the nivolumab/ipilimumab combination is very different from a TKI like cabozantinib. We are mainly talking about autoimmune side effects. So, if we look at the CheckMate-214 trial, 60% of patients required frequent treatment with corticosteroids, which is, in my view, a relatively higher use of steroids, more than I have practiced in my clinic with single-agent nivolumab.

TKI Therapy Versus I-O Therapy in mRCC

In the CABOSUN trial, which was a phase II randomized trial of almost 160 patients comparing cabozantinib with sunitinib, cabozantinib was clearly superior to sunitinib in terms of progression-free survival, which was also confirmed by independent radiological assessment. The progression-free survival with cabozantinib was 8.6 months compared with 5.3 months for sunitinib. And this was a relatively high-risk patient population with only intermediate- and poor-risk patients being included, butmore notably&mdash;30% of patients had bone metastases. So, after confirming superiority of cabozantinib over sunitinib by an independent radiologic assessment, in my mind, cabozantinib is a drug of choice for this patient.

Going back to the question of sunitinib versus pazopanib, I did not choose pazopanib in this patient, because we already have data from the COMPARZ trial from a few years ago, where sunitinib was found to be equivalent to pazopanib or vice versa, as far as progression-free survival was concerned. So, we know that pazopanib and sunitinib are very comparable as far as progression-free survival is concerned, and cabozantinib is clearly superior to sunitinib from the CABOSUN trial. The extrapolation of the data basically leads me to believe that cabozantinib is also superior to pazopanib, with the caveat that these 2 drugs have not been compared head-to-head in a randomized clinical trial.

Clinical Rationale for TKI Choice in mRCC

Would I use a different dose of cabozantinib in a frailer patient? I think so. If I&rsquo;m seeing a 79-year-old frailer patient than the patient I just described, I think I would start with cabozantinib at 40 mg daily and maybe further decrease the dose as long as patient is responding. So, yes, I think decreasing the dose of cabozantinib is often a wise decision in patients where we think 60-mg daily dosing may cause excessive toxicities.

Would I make a different choice as far as treatment selection is concerned for a patient whose tumor is expressing PD-L at more than 1%? I think so. If I look at the data from the CheckMate-214 trial, almost 300-plus patients out of almost 1000 patients whose tumors were expressing PD-L1 at more than 1% had dramatic progression-free survival benefit compared with sunitinib. The PFS with the combination was 22 months compared with 5 months with sunitinib. So, given these data, I do not have any doubt that PD-Lexpressing tumors or patients with PD-L&ndash;expressing tumors need treatment with ipilimumab/nivolumab combinationswithout any question.

Treatment for Frail or PD-L1-Positive mRCC

What do I do when this patient experiences disease progression on cabozantinib? I think I base my decision or therapy selection for the second line, when second-line therapy is concerned, on the volume of disease or rapidity of disease progression. If the disease is progressing mildlythe pace is slow, indolent&mdash;I would choose nivolumab, because then I&rsquo;m not really worried about not experiencing a progression-free survival benefit with nivolumab.

On the other hand, if this disease is rapidly progressing with multiple new lesions, including liver lesions, on cabozantinib, I would choose the lenvatinib/everolimus combination, because that combination has been shown to have remarkably high rates of objective response, which have not been seen by any other monotherapy so far in metastatic renal cell carcinoma.

Therapeutic Approach for Metastatic Renal Cell Carcinoma

Case of Rapidly Progressing mRCC

Choosing Therapy for mRCC

TKI Therapy Versus I-O Therapy in mRCC

Clinical Rationale for TKI Choice in mRCC

Treatment for Frail or PD-L1-Positive mRCC

Sequencing Therapy for mRCC Progression